The extracellular matrix plays an important role in tissue structure and in cell behavior, function and differentiation. Many of the effects of matrix macromolecules are mediated by binding sites or receptors on the cell surface. Endothelial cell morphogenesis, as occurs in angiogenesis or embryonic vasculogenesis, involves a series of events that include cell migration, tubule formation, and division. Folkman, J. and Haudenschild, C. Nature, 288:551-556 (1980); Poole, T. and Coffin, J. J. Exp. Zool., 251:224-231 (1989). Many experimental studies have indicated that the interaction of endothelial cells with the extracellular matrix plays a key role in these processes. Madri, J. and Pratt, B. J. Histochem. Cytochem., 34:85-91 (1986); Furcht, L. Lab. Invest., 55:505-509 (1986); Ingber, D. J. Cell. Biochem., 47:236-241 (1991). For example, the integrin family of matrix receptors and a 67-69 kilodalton (kDa) laminin receptor appear to mediate at least part of this influence of matrix on the behavior of endothelial cells. Charo et al., J. biol. Chem., 262:9935-9938 (1987); Dejana et al., J. Cell Biol., 107:1215-1223 (1988); Grant et al., Cell, 58:933-943 (1989); Basson et al., Dev. Biol., 146:186-197 (1990); Defilippi et al., J. Cell biol., 114:855-863 (1991).
Hyaluronan is a high molecular weight, highly anionic polysaccharide found in the extracellular matrix and at cell surfaces. It is composed of 200-10,000 disaccharides of B-1,4-glucuronate-B-1,3-N-acetylglucosamine, and has a molecular weight in the range of from about 6.times.10.sup.4 to about 1.2.times.10.sup.7. Hyaluronan is a major component of matrices in which cells proliferate and migrate during embryonic morphogenesis and differentiation, tissue regeneration, tissue healing, tissue remodeling and tumorigenesis. See Toole, B., Cell Biology of Extracellular Matrix (F. Hay, ed.) pp. 259-294 (1981).
The pericellular region surrounding migrating tips of newly forming capillaries is enriched in hyaluronan. Ausprunk et al., Am. J. Pathol., 103:367-375 (1981). It has also been shown that capillaries of the chorioallantoic membrane begin to form in hyaluronan-rich areas but the level of hyaluronan surrounding the capillaries rapidly decreases thereafter. Ausprunk et al., Am. J. Pathol., 103:367-375 (1981); Ausprunk, D., Am. J. Anat., 177:313-331 (1986). Other investigations have shown that blood vessel formation does not occur in hyaluronan-rich zones and that endothelial cell growth is inhibited by polymeric hyaluronan. Feinberg, R. and Beebe, B., Science, 220:1177-1179 (1983); West, D. and Kumar, S., Exp. Cell Res., 183:179-196 (1989). However, oligosaccharides of hyaluronan containing 3-16 disaccharide repeats have been shown to stimulate blood vessel formation and endothelial cell growth. West, et al., Science, 228:1324-1326 (1985); West, D. and Kumar, S., Exp. Cell Res., 183:179-196 (1989).